A field based evaluation of adverse events following MenAfriVac®vaccine delivered in a controlled temperature chain (CTC) approach in Benin

Introduction An estimated one hundred million African meningitis belt residents have received MenAfriVac®meningococcal serogroup A conjugate vaccine. Since October 2012 the vaccine has been licensed for use in a controlled temperature chain (CTC) approach, at temperatures of up to 40°C for up to four days. The Benin Ministry of Health conducted a pilot evaluation in one of its 34 health districts to assess whether the CTC approach was associated with increased adverse events following immunisation (AEFIs). Methodes We compared the occurrence of AEFIs during the 5 days following immunisation for 4 villages in the district using the CTC approach to 4 villages in another district using the traditional approach (vaccine kept at +2 to +8°C). Severe events resulting in hospitalisation or death of non-interviewed household members also were recorded. Results We included 1000 persons in the CTC and 999 in the non-CTC group. Only mild and transient AEFIs were noted in both groups, such as pain at injection site or fever. Compared to the non-CTC group, the CTC group had similar or lower rates of AEFIs and the occurrence of AEFIs in both groups was similar to that indicated in the vaccine package insert. No case of hospitalisation or death occurred among interviewed and non-interviewed household members. Conclusion The CTC approach, as implemented in Benin, was not associated with an increased rate of adverse events in the five days following immunisation, either when compared to a concurrent non-CTC population or to previous studies.


Introduction
MenAfriVac ® -manufactured by the Serum Institute of India Ltd -is a lyophilized vaccine containing 10 mcg of purified meningococcal A polysaccharide conjugated to 10 to 33 mcg of tetanus toxoid with the addition of mannitol, sucrose, and Tris(hydroxymethyl)aminomethane. It is the first Neisseria meningitidis serogroup A (NmA) conjugate vaccine specifically developed for use in the African meningitis belt [1]. From its introduction in late 2010 to the end of 2012 an estimated one hundred million individuals have received the vaccine [2]. The vaccine has been used in vaccination campaigns in Burkina Faso [3], Niger [4], Mali, Cameroon, Chad, Ghana, Nigeria, Senegal, Sudan and Benin. Preliminary findings suggest that the vaccine is highly effective in reducing NmA carriage [5] and disease in Africa [6].
Data also suggest that the vaccine is safe as delivered in the traditional cold chain. The MenAfriVac® package insert [7] and studies in India [8] and Mali [9] reported that the most common identified side effects at one week were pain at the injection site, diarrhea, loss of appetite, and fever.
On October 26, 2012, The Drugs Controller General of India (DCGI) granted approval to license the vaccine for use in a controlled temperature chain (CTC) approach at temperatures of up to 40°C for up to four days [7], followed by WHO prequalification for this approach [10]. The CTC approach has the potential to reduce the logistical complexity of maintaining vaccines in the +2 to +8°C temperature range up to the moment of injection of the vaccine and thus increase vaccine access to remote areas [11]. Based on its review of available clinical trial safety data, the WHO Global Advisory Committee on Vaccine Safety concluded that MenAfriVac ® showed a favourable safety profile [12]. Moreover, pharmacovigilance activities implemented to monitor Adverse Events Ministry of Health (MoH) decided to pilot test the CTC approach, the first country globally to evaluate this approach. The present evaluation, integrated into a reinforced pharmacovigilance monitoring system, was designed to assess whether the vaccine delivered in the CTC approach resulted in unexpected AEFIs. Due to logistical and budget constraints, we did not attempt to detect rare (0.1-0.01%) or very rare events (<0.01%) or benign effects that have not been described previously in the literature.

Methods
Ethical issues: the Drugs Controller General of India (DCGI) granted approval to license the vaccine for use in a CTC approach.
The Benin MoH determined that the current activities did not require institutional review board approval based on a) use of an on-label approach and b) its assessment that the decision to implement and conduct a quality control evaluation of the CTC approach fell within its public health authority as part of routine immunization activities  [8,17], three in African subjects [9,14,15], and two reports from the WHO Global Advisory Committee on Vaccine Safety [12,13], plus the product package insert [7]. Because of the small number of trials, all were reviewed and used for comparison and identification of potentially important AEFIs; however, our results were compared formally only to data from the definitive licensing trials [8,9].

Discussion
This is the first field-based evaluation of the CTC methodology during a public health immunisation campaign. The NmA conjugate vaccine MenAfriVac ® specifically has received licensure for this approach based on demonstration of vaccine stability, and no novel adverse events were expected. However, because unexpected events may occur, confirmation of this assumption was necessary.
This is particularly true when implementing vaccine outside of a controlled study in a public health campaign. As a new vaccine, relatively limited post-licensure safety data are available for MenAfriVac ® . We found no cases of hospitalisation or death, no increased occurrence of adverse events in persons receiving vaccine through the CTC versus the routine cold chain approach, and no increased incidence of adverse events in the CTC group compared to historical data for MenAfriVac ® . These findings provide some initial support for the CTC approach and thus support the safety record of MenAfriVac ® [10][11][12][13]. To compare more easily AEFI incidence rates with data from the literature, where AEFI incidence rates usually are presented as percentages over a four or seven day period, we compared a subset of our data corresponding to day 4 and day 5 cohorts to previous data from the literature [8,9] or the MenAfriVac ® package insert [7] ( Table 6), and again found favourable results for the CTC approach. The CTC approach allows for exposure to ambient temperatures for up to 4 days, or 96 hours.
In our setting, the actual exposure duration usually was much shorter, with a mean of 20 hours, and none of the exposures exceeded the recommended limit even if this limit was approached.
Additionally, we did not see evidence for increased fever or other outcomes as exposure duration increased. These data confirm the practicality of the CTC approach, including that the exposure duration limit in the package insert is likely to be sufficient to achieve objectives during a campaign setting.

Conclusion
Following use of the CTC approach with MenAfriVac ® in a public health immunization campaign, occurrence of clinical outcomes during the first 5 days following immunization was no higher than in a comparison district using the traditional cold chain approach or outcomes reported in previous clinical trial settings. This initial study supports use of MenAfriVac ® with the CTC approach but additional studies are needed before more routine roll-out.

Competing interests
Christoph

Acknowledgments
We would like to thank Simona Zipursky (PATH) for her guidance at all stages of the evaluation, Olivier Ronveaux (WHO) for his critical input into the report, the team of field investigators, MoH Benin field staff who facilitated the field implementation phase and colleagues at WHO and UNICEF country office who provided input to the evaluation and report.
Page number not for citation purposes 7   Tables and figures   Table 1: Overview of villages that delivered MenAfriVac ® with and without a controlled temperature chain (CTC), Benin 2012